In August of 2023, the Food and Drug Administration (FDA) released a final guidance document that serves to assist Institutional Review Boards (IRBs), Investigators and Sponsors in their roles and responsibilities related to the Informed Consent process. This document serves as a finalization to the FDA’s draft guidance issued in July 0f 2014 entitled “Informed Consent Information Sheet” and supersedes previously released guidance documents, including the FDA’s “A Guide to Informed Consent”, which was released in September of 1998.
ICF Summary & Background
It is not uncommon to hear informed consent referred to as the “informed consent process”. This is because the signing of the Informed Consent Form (ICF) entails far more than just a signature. According to the FDA, the informed consent process begins with advertisements used to recruit subjects. For this reason, it is important that any information provided in such advertisements be consistent with the ICF document and contain only the information needed for a subject to confirm their interest and potential eligibility for the study.
After identification of a potential subject, an investigator, or someone knowledgeable about the study and able to answer questions about the research, should hold a consent discussion with the subject, or their legally authorized representative (LAR), about the research to be conducted. Often times, this discussion is lengthy and can take place over a number of days, weeks, clinic visits or phone calls between the investigator and the subject. It requires adequate time for the subject to interpret the information presented and make an informed decision about their participation, along with time for the subject to ask questions.
The ICF process does not end with subject signature and enrollment. In fact, the informed consent process continues throughout the length of the subject’s participation, requiring investigators to share any new or updated safety information that has come to light.
Requirements and Exceptions
The process of informed consent and the ICF document must meet 21 CFR 50.20 requirements and include the basic elements of informed consent required by 21 CFR 50.25. However, there are some exceptions to this requirement, including certain life-threatening situations, military operations, or public health emergencies (21 CFR 50.23) or situations involving emergency research (21 CFR 50.24). The FDA does not limit the authority of a physician to provide emergency medical care to the extent the physician is permitted to do so under applicable Federal, State, or local law.
- Free of coercion and undue influence
- Information presented to the subject must be in a clear, concise manner, which does not hold false promises of benefit. Any payment made to subjects should be approved by the IRB as non-coercive.
- Understandable language
- Information provided to the subject, or their LAR, must be presented in a language understandable to the subject and at a level they can comprehend.
- Free of exculpatory language
- The ICF document must be free of any language that implies the investigator, sponsor, site or its agents are not liable for negligence.
At a minimum, an ICF must include a description of the study, expected/potential risks and discomforts, expected/potential benefits, alternative procedures or treatments available to the patient, confidentiality principles, compensation and treatment in the event of injury, study contact information, and a statement of voluntary participation.
Additional ICF elements may be applicable depending on the research to be conducted, according to 21 CFR 50.25(b). Such elements may include a statement of unforeseeable risk, involuntary termination of subject’s participation, additional cost to subjects, consequences of a subject’s decision to withdraw, providing significant new findings to subjects, and the approximate number of subjects involved in the study.
Under 21 CFR 50.27, a short form may be used in a situation where the required elements of the ICF are presented orally, such as in a case where the subject or LAR is unable to read due to low literacy levels or visual impairment. Any information planned to be shared orally to support the use of a short form must be IRB approved.
All applicable clinical trials must, per FDA requirement, include the following statement exactly as written: “A description of this clinical trial will be available on https://www.ClinicalTrials.gov, as required by U.S. Law. This Web site will not include information that can identify you. At most, the Web site will include a summary of the results. You can search this Web site at any time.” Additional explanation may be provided, if deemed necessary.
A copy of the ICF, preferably signed, should be given to the person who signed the consent form. For circumstances where the consent does not occur in-person, a wet-ink or electronic signature must be obtained and the signed ICF sent to the investigator by mail, delivered by the subject (at their next scheduled visit) or sent electronically. The subject or LAR is also responsible for entering the date of signature on the ICF.
Certain circumstances, such as those involving no more than minimal risk, allow for the use of oral consent from a subject or their LAR, in which case no signature is required, and the consent process should be thoroughly documented in the subject’s case history and maintained under 21 CFR 312.62(b) or 21 CFR 812.140(a)(3).
As it relates to the informed consent process, the IRB is responsible for review of all informed consent materials, including recruitment materials (e.g. advertisements) and supplemental materials (e.g. schedule of assessments) to ensure their compliance with 21 CFR 50.25. In their review, the IRB must ensure all materials are free from coercive language and undue influence (21 CFR 50.20 and 56.111(a)(4)). If the study involves vulnerable populations, the IRB must ensure adequate safeguards are in place. It is the IRB’s role to consider if subjects should be informed of any financial relationships or interests associated with the investigation. In case of conflicting financial interests, the IRB should ensure subjects are adequately protected.
The planned process for consent should be submitted by the investigator to the IRB. The investigator should clearly state who will be responsible for conducting the consent process and what procedures will be followed. The IRB is authorized to observe or have a third party observe the consent process, as deemed necessary.
Any new information about the research or changes to the study that may affect the rights or welfare of subjects must be presented to the IRB. The IRB is responsible for determining if a revised ICF is required based on the new information. If so, the amended ICF must be approved by the IRB before implementation by the investigator. The revised ICF should be marked with a clear identifier to distinguish between the different versions.
Should a study be suspended, the IRB has the authority to require that information be provided to subjects if it adds to the protection of their rights and welfare. However, the IRB, sponsor and investigator have the shared responsibility of determining what information is shared. If a study is terminated, subjects should receive as much information as possible regarding the rationale behind the termination.
The investigator is responsible for obtaining the informed consent. They may delegate this responsibility to another individual who is qualified by education, training and experience, though the investigator is ultimately responsible for oversight of the designated individual and ensuring the informed consent was obtained in accordance with 21 CFR part 50. The individual obtaining consent should be knowledgeable about the clinical investigation and have the appropriate training and credentials to be able to answer any questions posed by the subject or LAR.
It is the investigator’s responsibility to submit the planned process for obtaining the informed consent to the IRB for approval. Any material intended for subjects as part of the informed consent process must also be approved by the IRB. No materials, including the ICF, may be shared with potential subjects until the IRB has granted all necessary approvals. It is also the investigator’s responsibility to submit any new information revealed during the course of the study to the IRB for approval before the changes are initiated within the conduct of the research. An exception to this rule may occur when necessary to prevent immediate harm to the subjects (21 CFR 56.108(a)(4)).
The investigator should consider including information related to financial relationships or interests within the consent form. For example, they may choose to disclose the source of funding for the study, information about a financial arrangement or interest of an institution or investigator and how it is being managed. If a potential or actual conflict of interest exists, the investigator should consider having another individual, who does not have a financial conflict of interest, be involved in the consent process or the investigator may choose to use independent monitoring for the consent process.
The sponsor may provide a template ICF to the investigator for use. However, the sponsor must make certain that the ICF is updated following any feedback from the FDA received on their IND or IDE application to satisfy the regulations at 21 CFR 50.25. Any modifications made to the ICF after initial IRB submission must be re-submitted and re-approved before starting the trial.
If the investigator chooses to use the sponsor’s ICF template, it is the sponsor’s responsibility to ensure that any modifications made by the investigator satisfy 21 CFR 50.25 regulations. Should the local IRB return with significant modifications to the ICF, the sponsor is expected to share the changes with all investigators and their respective IRBs.
The sponsor may choose to be present during the first procedure for an IND trial, whether it be to provide support to the investigator or to record study-related information for the experimental device. In this case, the sponsor should outline these activities in the informed consent form, particularly if the activities of the sponsor personnel will directly affect the subject(s).
The FDA’s role in reviewing informed consent materials is to consider the appropriate communication of anticipated risks and discomforts to the subjects, as well as other required elements as per 21 CFR 50.25. If the FDA determines that the informed consent documents are misleading or do not adequately explain the required information to the subjects, they may require further revisions to be made before the trial can proceed.
For Investigational New Drugs (INDs) and Biologics, the FDA does not necessarily require the submission of the ICF with the IND, however they may request it if deemed necessary for the trial to proceed safely. Typically, the FDA will want to review the ICF if the investigation involves a known unusual or serious toxicity or risk to subjects, a vulnerable population, an unusual study design, if the study is a post marketing safety clinical trial required by the FD&C Act section 505(o) to assess serious risk, involves asking subjects to forgo or delay known effective treatment for the disease, or if the FDA has other confidential or proprietary information not readily available to the IRB.
For Investigational Medical Devices which require an IDE, the sponsor must submit all informed consent documents to the FDA. The sponsor is required to correct any deficiencies noted by the FDA within the informed consent documents before the clinical trial can be initiated.
About the Author
Jessica Connolly assists in study management oversight within the Clinical Operations department as an Associate Project Manager. She works closely with sites, sponsors, and IRBs to assist in regulatory reporting during the study start-up phase. In addition, she works with sites and sponsors to ensure all Informed Consent documents meet regulatory requirements and assists with revisions as needed.
ClinChoice is a leading global Contract Research Organization (CRO), with over 3,700 clinical research professionals across North America, Asia, and Europe. For more than 27 years, ClinChoice has been providing high-quality contract research services to pharmaceutical, biotechnology, medical device, and consumer products clients, encompassing a broad range of services and therapeutic areas. ClinChoice offers cutting-edge, full-service solutions for Clinical Trials, Regulatory Affairs, Medical Device Safety, Toxicology, and Medical Affairs.